Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
Abstract
Excitation-contraction coupling in striated muscle requires proper communication of
plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic
reticulum within junctional membrane complexes. Although previous studies revealed
a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2
(JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role
in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process
in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients
with hypertrophic cardiomyopathy.To elucidate the role of JPH2 in the heart, we developed
a novel approach to conditionally reduce JPH2 protein levels using RNA interference.
Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which
caused heart failure and increased mortality. JPH2 deficiency resulted in loss of
excitation-contraction coupling gain, precipitated by a reduction in the number of
junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic
reticulum distance.Loss of JPH2 had profound effects on Ca2+ release channel inactivation,
suggesting a novel functional role for JPH2 in regulating intracellular Ca2+ release
channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin
RNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin
in intracellular Ca2+ release in the heart.
Type
Journal articleSubject
Cell MembraneIntercellular Junctions
Animals
Mice, Transgenic
Mice, Knockout
Mice
Calcium Channels
Ryanodine Receptor Calcium Release Channel
Membrane Proteins
RNA, Small Interfering
Myocardial Contraction
Heart Failure
Gene Knockdown Techniques
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https://hdl.handle.net/10161/20330Published Version (Please cite this version)
10.1161/CIRCULATIONAHA.110.006437Publication Info
Van Oort, RJ; Garbino, A; Wang, W; Dixit, SS; Landstrom, AP; Gaur, N; ... Wehrens,
XHT (2011). Disrupted junctional membrane complexes and hyperactive ryanodine receptors after
acute junctophilin knockdown in mice. Circulation, 123(9). pp. 979-988. 10.1161/CIRCULATIONAHA.110.006437. Retrieved from https://hdl.handle.net/10161/20330.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Andrew Paul Landstrom
Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and
young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained
death syndromes. As a clinician, he is trained in pediatric cardiology with a focus
on arrhythmias and genetic diseases of the heart. He specializes in caring for patients
with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia,

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